Biomarkers of acute lung injury: Worth their salt?
Authors:
Alastair Proudfoot, MRCP
Matthew Hind, MRCP PhD
Mark JD Griffiths, MRCP PhD
Institution:
Adult Intensive Care Unit
Royal Brompton Hospital
Sydney Street
London, SW3 6NP
United Kingdom
Corresponding author: Mark Griffiths
Telephone:
+44 (0) 207 351 8523
Fax:
+44 (0) 207 351 8524
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Key words: biomarker, acute lung injury (ALI), acute respiratory distress syndrome
(ARDS), ventilator induced lung injury,
Abstract
The validation of biomarkers has become a key goal of translational biomedical research. The
purpose of this article is to discuss the role of biomarkers in the management of acute lung
injury (ALI) and related research. Biomarkers should be sensitive and specific indicators of
clinically important processes and should change in a relevant timeframe to affect recruitment
to trials or clinical management. We do not believe that they necessarily need to reflect
pathogenic processes. We critically examine current strategies used to identify biomarkers
and which, owing to expedience, has been dominated by reanalysis of blood derived markers
from large multicentre phase 3 studies. Combining new and existing validated biomarkers
with physiological and other data may add predictive power and facilitate the development of
important aids to research and therapy.
Introduction
The validation of biomarkers has become a central tenant of translational biomedical research.(AGP
Curr Op 2011 in press) The purpose of this article is to discuss the role of biomarkers in the
management of acute lung injury (ALI) and related research. We shall not present a state of the art
review of the field of all the biomarkers that have been investigated in this field, excellent examples
of which have been produced recently.1,2 Rather we shall question current strategies to identify
biomarkers and whether what has been achieved thus far has advanced the field.
The natural history of acute lung injury
Acute lung injury and its more severe counterpart the acute respiratory distress syndrome (ARDS:
defined in table 1) describe the radiographic and physiological characteristics of patients with acute
lung failure.3 A combination of tissue injury and inflammation affecting the gas exchange surface of
the lung, the alveolar-capillary membrane, causes high permeability pulmonary oedema. The
presence of a protein-rich inflammatory exudate in the airspace impairs surfactant function4.The
resulting collapse and consolidation of the lung causes profound hypoxia because inflammatory
mediators induce changes in the control of vascular tone that disable hypoxic pulmonary
vasoconstriction.5 Loss of pulmonary capillary surface area associated with lung destruction and
occlusion of the vascular bed by intravascular thrombosis, increases the anatomical dead space,
itself associated with a poor outcome,6 and giving rise to carbon dioxide retention. Host factors,
both inherited7,8 and acquired, influence individual susceptibility (for example, excessive alcohol
consumption predisposes, whilst diabetes mellitus protects). Precipitating causes or risk factors
which often “hunt in packs” either affect the lung directly (pneumonia, aspiration of stomach
contents and thoracic trauma) or cause ALI indirectly through a systemic inflammatory response
syndrome (SIRS) associated with multiple organ dysfunction, exemplified by severe sepsis and
transfusion related ALI. These causes to a large part determine the initial clinical course and
outcome, but most patients require invasive mechanical ventilation in an intensive care unit to
maintain adequate gas exchange.
Relatively little is known about the processes that determine the resolution of
inflammation,injury and subsequent lung repair.9 The three-phase pathological model of ALI
(exudative, proliferative and fibrotic) and the assertion that fibrosis is an inevitable consequence of
unresolved inflammation are gross over-simplifications. Fibrosis is evident histologically as early as a
week after the onset of the disorder10 and procollagen III peptide, a precursor of collagen synthesis,
is elevated in the broncho-alveolar lavage (BAL) fluid of ARDS patients at the time of tracheal
intubation.11 Similarly, whilst several pro-inflammatory mediators are pro-fibrotic, distinct patterns
of gene expression are associated with these processes in the injured lung.12 However, the
development of pulmonary fibrosis in a patient with ALI predicts the requirement for prolonged
respiratory support and a poor outcome.13
Despite years of concerted effort and very many clinical trials, a minority of which have been
capable of producing a definitive result, there are no treatments that improve the outcome of
patients with ALI.14 What has become evident both in this field and in critical care in general, is the
extent and importance of iatrogenic injury. Hence half of ALI arises in patients who were subjected
to mechanical ventilation for another reason: the four major culprits being mechanical ventilation
that targets normal blood gas parameters, transfusion of blood products, excessive fluid
resuscitation and hospital acquired pneumonia. Accordingly, recent epidemiological evidence
suggests that targeting hospital acquired injury can halve the incidence of ARDS despite an increase
in patients' severity of illness, the number of comorbidities and the prevalence of major ARDS risk
factors.15
Hence studying patients with ALI is a challenge because the syndrome is the end result of an
almost infinite variety of scenarios. These range from young fit patients with severe pneumonia or
thoracic trauma to elderly patients who fail to recover from routine procedures, suffer
complications, require respiratory support because of a combination of a chronic cardio-respiratory
condition and hospital-acquired pneumonia and ultimately develop ARDS on a ventilator. As a
consequence the water is muddied both by heterogeneity in the host and the risk factors, and by the
variety of other co-incident processes. Furthermore, it is often difficult to define precisely when the
syndrome started which may have a dramatic effect on measured variables in cases where the
condition changes rapidly. Finally, variable management regimens may contribute to patient
heterogeneity, both in the face of clear evidence (e.g. poor adherence to low tidal volume
ventilation)16 and where evidence is lacking (e.g. in the use of adjuncts to respiratory support like
prone positioning, inhaled nitric oxide and high frequency oscillation). Conversely, critically ill
patients are closely monitored, physiological data are electronically stored and their clinical
condition may paradoxically render them more amenable to undergoing invasive procedures.
Why invest in biomarkers for ALI?
Biomarkers are potentially useful as guides to clinical management and as research tools. In the
clinical setting there is a high premium on biomarker data being easily and safely obtained within a
timeframe that is relevant to the disease process (Box 1). For example, an indicator of poor
prognosis that may encourage referral to a specialist centre would need to be available within hours,
whereas a marker of ventilator-associated lung injury (VALI) that was being used to fine-tune
ventilator settings would have to be “turned around” within minutes. No biomarkers that are
currently available have penetrated routine clinical practice with the possible exception of the use of
procalcitonin (PCT) to diagnose sepsis in critically ill patients and to guide their antibiotic therapy.
Sepsis syndromes commonly both cause and complicate ALI; ventilator associated pneumonia in
particular frequently exacerbates ALI causing diagnostic difficulty. Procalcitonin levels correlate with
severe sepsis and bacteraemia,17 but did not consistently differentiate survivors from nonsurvivors.18 A PCT-based algorithm guiding initiation and duration of antibiotic therapy in critically ill
patients with suspected bacterial infection was associated with a 23% relative reduction in antibiotic
exposure with no significant increase in mortality.19 Aside from this role in limiting antibiotic
exposure, a recent review of the role of PCT in diagnosing ventilator associated pneumonia
concluded that the biomarker showed good specificity but low sensitivity.20
Clinical research in ALI has used biomarkers as surrogate outcomes for early phase 2 studies
and may in the future be valuable in categorising patients into subgroups that are predicted to be
most likely to benefit from particular interventions. For example in the single-centre “BALTI 1” study
40 patients with ALI were enrolled to demonstrate the ability of 7 days of treatment with
intravenous salbutamol to decrease extravascular lung water measured by thermodilution (PiCCO).21
The resolution of pulmonary oedema is central to recovery from ALI as it entails deffervescence of
air space inflammation and restoration of a functioning alveolar-capillary membrane, and
extravascular lung water correlated with mortality in a large cohort of critically ill patients.22 Hence,
the use of a surrogate rather than a clinical end-point, such as ventilator free days or intensive care
unit length of stay, decreased the recruitment target to what was achievable for a single centre.
However, with hindsight it is arguable whether this positive result then justified the investment in 2
phase 3 large multi-centre trials.14
The use of biomarkers to refine patient populations such that clinical trials will be most likely
to provide a definitive answer requiring the fewest patients, is particularly appealing for application
to research involving patients with a heterogeneous syndrome like ALI. For example reanalysis of the
ARDS Network ARMA study revealed that the beneficial effect of low tidal volume on mortality was
evident only in patients with higher plasma levels of soluble receptor of advanced glycation end
products (sRAGE) at enrolment. The inference is that more severe lung epithelial injury may
predispose patients to more severe harm associated with mechanical ventilation, however whilst
RAGE is highly expressed in the lung compared with other organs and particularly on alveolar type I
epithelial cells23, it is also expressed on vascular endothelium and is upregulated in association with
inflammation.24 By extension should subsequent studies that attempt to make mechanical
ventilation more protective, in which the control arm would receive the now standard low tidal
volume ventilation strategy thereby driving up the number of patients required to power the study
on mortality, only enrol patients with an elevated initial circulating sRAGE concentration? It is
probably too early to make this recommendation but this model of reanalysing samples and data
from large studies to refine patient populations for future trials offers some hope for carrying out
phase 3 studies over a reasonable time and manageable recruitment targets.
Characteristics of ideal biomarkers for ALI
Proposed criteria for characterising ideal biomarkers for ALI, most of which are self-explanatory are
listed in Box 1. It has been argued that biomarkers should inform or at least relate to the disease
pathogenesis.25 We disagree for philosophical reasons, why confuse elucidating mechanisms with
the pragmatic business of identifying biomarkers? We prefer as wide a definition as possible: for
example, the electrocardiograph has been one of the most useful biomarkers in medicine but not
much can be learnt about the pathogenesis of myocardial infarction through its study.
The current definition of ALI/ARDS is such that biomarkers of the established syndrome are
largely redundant. An exception would be a biomarker that was specific to the pathological process
described as diffuse alveolar damage. That is, a biomarker that could exclude patients from studies
who fulfilled the diagnostic criteria but who essentially have a distinct disease, which may have a
different natural history and specific treatment, for example eosinophilic pneumonia and pulmonary
embolism. Similarly, most studies have attempted to correlate selected biomarkers with disease
severity or death, which is potentially useful both clinically to help target resources and more
expensive or invasive management strategies and in helping to power research studies using
mortality as the primary outcome.
We propose that the use of biomarkers in a complex syndrome like ALI is most likely to be
effective when they are specific to an individual component or process that can be manipulated.
One productive approach has been to measure plasma and BAL fluid levels of mediators as a
reflection of systemic and pulmonary inflammation respectively. In samples from large multicentre
trials elevated levels of mediators like soluble tumour necrosis factor-alpha receptors (sTNFR) 1 &
2,26 soluble intercellular adhesion molecule-1,27 and interleukin (IL)-628 were associated with adverse
outcomes in patients with ALI. The limitations of this strategy are that these mediators have multiple
effects, have no specificity to the lung and there is no convincing evidence that manipulating the
inflammatory response benefits patients with ALI. Partly because of the realisation that VALI plays a
major part in the pathogenesis of ALI and as a result many large studies have been performed
examining the effects of ventilator strategies, a lot has been learnt about the responses of popular
biomarkers in patients undergoing protective and standard ventilation.2 Hence circulating mediators
of inflammation (sTNFR27, IL-6, -8 and -1029), indicators of epithelial cell injury (sRAGE30 and
surfactant protein-D31) and components of the coagulation system (protein-C and plasminogen
activator inhibitor-132) have all been promoted as biomarkers of VALI. However, because the
proposed mechanism whereby VALI kills patients is through the exacerbation of local injury and
inflammation, the mediators of which then leak into the systemic circulation causing multiple organ
dysfunction,33 it would be surprising if there was not considerable overlap between markers of VALI,
tissue injury, inflammation and a poor prognosis. In other words these biomarkers inevitably lack
specificity for individual processes or outcomes.
More recently the power of combining clinical parameters with a panel of traditional
biomarkers to predict mortality in patients with ALI using a variety of statistical techniques has been
examined in the large datasets and sample stores resulting from ARDS Network studies.34,35 In one of
the studies35, the six clinical predictors were: age, the underlying cause, APACHE III score, plateau
pressure, number of organ failures, and alveolar-arterial difference in the partial pressure of oxygen
measured at enrolment prior to randomization. Eight biomarkers were measured in baseline plasma
samples from enrolled patients that reflected endothelial and epithelial injury, inflammation, and
coagulation. A “reduced model” including just the APACHE III score, age, SP-D, and IL-8, performed
almost as well as that which included all parameters and biomarkers. However, the additional
predictive value of the plasma biomarkers added to the clinical predictors alone was modest; thus,
further work will be needed to test the value of these biomarkers over clinical predictors alone.
Furthermore, whilst the inclusion of biomarker data into a model improved the accuracy of mortality
prediction, the predicted risk of death for the patient, who ultimately died remained lower than 50%
suggesting that important contributors to mortality have been accounted for by the model.34
Model systems for biomarker development
An alternative approach to examining clinical samples is to test the validity of existing or novel
candidate biomarkers using models systems, in which the signal-to-noise ratio is likely to be more
favourable and the time course of the biomarker’s response can be more precisely determined
(Figure 1). For this purpose we believe that human models are likely to be more useful than animal
models, despite the undoubted contribution of the latter to our understanding of the syndrome’s
pathogenesis.36,37 For example, at the most basic level comparative proteomic analysis between BAL
fluid from a patient and a mouse model of ALI identified only 21 homologous proteins.38
For an example of a human model of ALI, one lung ventilation (OLV), a technique required to
facilitate lung resection surgery, has been exploited to investigate potential biomarkers of VALI.39,40
One-lung ventilation may be a useful model of VALI because it is associated with a smaller lung
volume available for ventilation, localised lung collapse or atelectasis and impaired oxygenation,
resulting in exposure of the ventilated lung to volutrauma, repeated opening of collapsed airspaces
(atelectotrauma) and a high inspired oxygen concentration. High tidal volume and airway pressure
during OLV correlated with the development of ALI in patients undergoing lung resection41-44 and the
incidence of ALI after lung resection over a 5-year period was lower, compared to a historical control
group, after introduction of a ‘protective’ OLV protocol.45 In small prospective studies the use of low
tidal volume OLV was associated with reduced biomarkers of pulmonary and systemic
inflammation.46,47 Finally, in an observational prospective study of 30 patients, exhaled breath
condensate pH was reduced within minutes of starting OLV suggesting that, as a direct means of
sampling the milieu of the lung. Whilst, in the clinical setting the effect of changing ventilator
settings may be drowned by co-incident inflammatory processes in the lung it may hold promise as a
non-invasive real-time biomarker of VALI, despite the mechanism by which exhaled breath
condensate acidification being poorly understood.
Future directions
We propose that the most useful biomarker development and use will involve novel therapies and
support modalities. For example, novel extra-corporeal carbon dioxide removal (ECCO2R) systems
that will make these techniques safer, cheaper and more readily available should stimulate the
search for novel biomarkers for VALI. The demonstration that gold standard low tidal volume
protective ventilation was associated with signs of over-distension on CT scanning, elevated plasma
markers of inflammation and a plateau airway pressure greater than 28 cmH2O in approximately a
third of patients with ARDS provided a readily identifiable population on which the effectiveness of
novel ECCO2R devices could be tested.48 In a subsequent study, a group of patients with ARDS was
identified by their having a plateau airway pressure greater than 28 cmH2O in who low tidal volume
ventilation was presumed to be causing significant VALI. For these patients a novel ECCO2R device
(DeCap) enabled the research team to decrease tidal volume further targeting a plateau airway
pressure of less than 25 cmH2O, which was associated with a lower radiographic index of lung injury
and lower levels of lung derived inflammatory cytokines.49
Specific biomarkers of other component processes of ALI other than inflammation, tissue
injury and VALI should be developed and incentive for this will be greatly increased as novel
therapeutics are introduced. For example, recent advances in the understanding of the pathogenesis
of pulmonary fibrosis and endothelial barrier function, leading to the development of novel
therapies should be adopted by the field of ALI. Biomarkers combined with physiological and
potentially genomic data should be used to identify patient groups for research studies and
individuals who are mostly likely to gain from targeted therapies.
Conclusions
Biomarker development for patients with ALI is an essential component of progress in translational
medicine in this frustrating area. Biomarkers should be sensitive and specific indicators of clinically
important processes and should change in a relevant timeframe to affect recruitment to trials or
clinical management. They do not necessarily need to reflect pathogenic processes. Combining
biomarkers with physiological and other data may add predictive power and aid the development of
important aids to research and therapy.
Abbreviations
ALI, acute lung injury; ARDS, acute respiratory distress syndrome; SIRS, systemic inflammatory
response syndrome; PCT, procalcitonin; BAL, broncho-alveolar lavage; sTNFR, soluble tumour
necrosis factor-alpha receptors; VALI, ventilator associated lung injury; OLV, one lung ventilation;
ECCO2R, extra-corporeal carbon dioxide removal;
Competing interests
M.G. received consultancy fees, educational grants and served on advisory boards for
GlaxoSmithKline (Middlesex, UK). A.P. and M.H. have not disclosed any potential conflicts of interest.
Acknowledgements
The work was funded and supported by the NIHR Respiratory Disease Biomedical Research Unit at
the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London. The views
expressed in this publication are those of the authors and not necessarily those of the NHS, the
National Institute for Health Research or the Department of Health.
Timing
ALI
ARDS
Oxygenation
PaO2/FiO2 < 300mmHg or
40kPa
Acute
PaO2/FiO2 < 200mmHg or
27kPa
Chest Radiograph
Exclusion of cardiogenic
pulmonary oedema
Bilateral opacities consistent with
pulmonary oedema
PAOP <18mmHg if measured or
no clinical evidence of left atrial
hypertension
Table 1: NAECC definition of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome
(ARDS)3
PaO2/FiO2 – arterial partial pressure of oxygen/ inspired oxygen fraction
PAOP – pulmonary artery occlusion pressure
•
Measurement is safe & feasible in the critically ill
•
Sensitive, reproducible & specific
•
Timely
•
Modified by an effective intervention to change the target outcome of interest
Box 1: Proposed characteristics of an ideal biomarker for acute lung injury
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Figure Legends:
Figure 1: ALI Biomarkers: Ventilator Induced Lung Injury experimental models and observational
clinical studies
A. Experimental models: High tidal volume ventilation (tidal volume in excess of 10 ml/kg
predicted body weight) may be used to induce lung injury but, through the overspill of
inflammatory mediators into the circulation (biotrauma), multiple organ dysfunction may
follow. Biomarkers may be assayed directly from the lungs (black), from the circulation (red)
or as indices of dysfunction related to other organs (green).
B. Observational clinical studies: Injured lungs are susceptible to damage even when gold
standard mechanical ventilation (tidal volume 6ml/kg predicted body weight) is used.
However, in the presence of existing lung injury several processes are likely to be
concurrent, both affecting the lungs directly (inflammation, tissue injury, coagulation,
fibrosis) and indirectly from other affected organs (sepsis). Hence the relationship between
any biomarker and ventilator settings is likely to be obscured by multiple unknowns.